Mammals are generally thought to have five basic categories of taste perception: salt, sour, sweet, bitter and umami (monosodium glutamate) (for review, see Lindemann, Physiological Reviews 76:719-766 (1996); Herness and Gilbertson, Annu Rev. Physiol. 61:873:900 (1999)). The taste signals are sensed by specialized taste receptor cells (TRCs), which are organized into taste buds. Each taste bud comprises between about 50 and 100 individual cells grouped into a cluster that is between 20 and 40 microns in diameter. Nerve fibers enter from the base of the taste bud and synapse onto some of the taste receptor cells. Typically, a single TRC contacts several sensory nerve fibers, and each sensory fiber innervates several TRCs in the same taste bud (Lindemann, supra).
TRCs of most, if not all, vertebrate species possess voltage-gated sodium, potassium, and calcium ion channels with properties similar to those of neurons (Kinnamon & Margolskee, Curr. Opin. Neurobiol. 6:506-513 (1996)). Different types of primary tastes appear to utilize different types of transduction mechanisms, and certain types of tastes may employ multiple mechanisms which may reflect varying nutritional requirements amongst species (Kinnamon & Margolskee, supra).
Bitter and sweet taste transduction are thought to involve cAMP and IP3 (Kinnamon & Margolskee, supra). The bitter compound denatonium causes calcium ion release from rat TRCs and the rapid elevation of IP3 levels in rodent taste tissue (Id., citing Bernhardt et al., J. Physiol. (London) 490:325-336 (1996) and Akabas et al., Science 242:1047-1050 (1988)). Since denatonium cannot pass the cell membrane, it has been suggested that it may activate G-protein-coupled receptors, whereby the α and/or βγG protein subunits would activate phospholipase C, leading to IP3 generation and the release of calcium ions (Kinnamon & Margolskee, supra).
In recent years, a taste-specific G protein termed “gustducin”, which is homologous to the retinal G protein, transducin, has been cloned and characterized (Id., citing McLaughlin et al., Nature (London) 357:563-569 (1992)). It is believed that gustducin plays a direct role in both bitter and sweet transduction. For example, gustducin and subunit (∝-gustducin) null (knockout) mice had a reduced aversion to bitter compounds. Unexpectedly, the mice also exhibited a preference for sweet compounds suggesting involvement of gustducin in sweet transduction.
Recent biochemical experiments have demonstrated that taste receptor preparations activate transducin and gustducin in response to denatonium and other bitter compounds (Ming et al., Proc. Natl. Acad. Sci. USA 95:8933-8 (1998)).
To thoroughly understand the molecular mechanisms underlying taste sensation, it is important to identify each molecular component in the taste signal transduction pathways. The present invention relates to the cloning of an ion channel, TRP8 (transient receptor potential channel 8), that is believed to be involved in taste transduction and may be involved in the changes in intra-cellular calcium ions associated with bitter taste perception.